Which adjuvant treatment for patients with BRAFV600-mutant cutaneous melanoma?

Treatment of patients with melanoma has considerably improved over the past decade and more recently with adjuvant therapies for patients with American Joint Committee on Cancer (AJCC) stage III (loco-regional metastases) or IV (distant metastases) totally resected melanoma, in order to prevent recurrence. In the adjuvant setting, two options are available to patients with BRAFV600-mutant AJCC stage III totally resected melanoma: anti-PD-1 blockers (nivolumab or pembrolizumab) or BRAF plus MEK inhibitors (dabrafenib plus trametinib). In the absence of comparative studies, it is difficult to determine which of these options is best. Our aim was to review published studies focusing on the management of patients with BRAFV600-mutant melanoma in the adjuvant setting. We also reviewed the main clinical trials of BRAF plus MEK inhibitors and immunotherapy in advanced (i.e. unresectable metastatic) BRAF-mutant melanoma in an attempt to identify results potentially affecting the management of patients on adjuvants. More adverse events are observed with targeted therapy, but all resolve rapidly upon drug discontinuation, whereas with immune checkpoint blockers some adverse events may persist. New therapeutic strategies are emerging, notably neoadjuvant therapies for stage III patients and adjuvant therapies for stage II patients; the place of the adjuvant strategy amidst all these options will soon be re-evaluated. The choice of adjuvant treatment could influence the choice of subsequent treatments in neo-adjuvant or metastatic settings. This review will lead clinicians to a better understanding of the different adjuvant treatments available for patients with totally resected AJCC stage III and IV BRAFV600-mutant melanoma before considering subsequent treatment strategies.

[Panniculitis during BRAF inhibitor and/or MEK inhibitor therapy: A new case report and literature review]. / Hypodermite sous inhibiteur de BRAF et/ou inhibiteur de MEK : revue de la littérature à partir d'une nouvelle observation.

INTRODUCTION: BRAF inhibitors±MEK inhibitors can cause panniculitis. Since the initial case described in 2012 by Zimmer et al., some sixty further cases have been reported. Based on a clinical study and a recent and complete review of the literature, we set out in detail the characteristics of panniculitis occurring during BRAF and MEK inhibition therapy as well as the treatment thereof. PATIENTS AND METHODS: A 25-year-old-patient followed for multi-metastatic melanoma and taking dabrafenib and trametinib consulted for the appearance, twenty-two days after the start of targeted therapy (TT), of panniculitis of the legs and forearms possibly induced by the TT after other causes had been ruled out. The TT had been continued following dose reduction and corticoid therapy for ten days, and complete resolution occurred after fifteen days. RESULTS: Fifty-three cases of panniculitis during BRAF±MEK inhibition therapy were analysed. The condition occurred mainly with BRAF inhibitors alone (especially vemurafenib), but it was also described with three combinations of BRAF and MEK inhibitors, regardless of age (median: 45 years), with a M/F ratio of 0.51, and in 50 % of cases, it occurred within the first month (time to onset: between 1 and 480 days). Non-specific biopsy is useful to rule out differential diagnoses. Symptomatic anti-inflammatory treatment, whether systemic or topical, may be given. In the absence of signs of severity, the TT may be continued. CONCLUSION: When panniculitis occurs during BRAF±MEK inhibitor therapy, the causal role of the TT must be considered after full etiological investigation. It is essential to determine whether a causal relationship exists in order to avoid unwarranted cessation of treatment.

TOXICAN: a guide for grading dermatological adverse events of cancer treatments.

PURPOSE: The dermatological toxicity of cancer treatments is frequent and sometimes debilitating. Its reference classification, the NCI-CTCAE (National Cancer Institute-Common Terminology Criteria for Adverse Events), is sometimes difficult to use and does not include yet the newest toxicities. Our objective was to create a guide, TOXICAN, based on the CTCAE, which is easy to use in everyday practice and which facilitates the recognition and grading of these dermatological toxicities. METHODS: This guide was developed by a working group ("GESTIM") comprising oncodermatologists, allergists, pathologists, and researchers from Nantes University Hospital. It was based on the dermatological toxicities found in the CTCAE and adapted to daily practice. These toxicities were grouped into categories and associated with photographs of typical cases to aid recognition. A simplified grading scale derived from the CTCAE was also created. This booklet was validated by means of user evaluation, and then the Delphi consensus method. RESULTS: We selected 32 dermatological toxicities, including 12 created by our group, sorted into 7 categories: skin rash, dry skin/pruritus, hyperkeratotic papules, palmoplantar changes, hair and nail changes, mucosal changes, and others. Our simplified grading scale only differed from the CTCAE for one item, urticaria. Three items were modified after evaluation by the user group and 11 after application of the Delphi method. CONCLUSION: The objective of our practical guide is to facilitate the use of the CTCAE for recognizing and grading dermatological toxicity of cancer treatments in order to provide optimal guidance for therapeutic adaptations. Its impact on clinical practice remains to be evaluated.

Development of brain metastases in patients with metastatic melanoma while receiving ipilimumab.

UNLABELLED: Ipilimumab is a monoclonal antibody blocking the inhibitory molecule CTLA4 expressed by activated T lympocytes, used for the treatment of metastatic melanoma. Recent studies have shown its potential efficacy on brain metastases. OBJECTIVES: To assess the development of brain metastases under ipilimumab and identify clinical, histological or evolving criteria related to the appearance of these metastases. A retrospective study was conducted in 52 patients treated with 4 cycles of ipilimumab 3 mg/kg every 3 weeks for unresectable stage III or stage IV melanoma between January 2011 and July 2013 in a Department of Dermato-Oncology. As no data has been find in the literature, the results were compared to our other cohort of patients treated with vemurafenib during the same period. Ten patients (21.7 %) developed brain metastases under ipilimumab in a median time of 6.58 months after treatment initiation. The multivariate analysis showed a lower rate of brain metastases in patients with acral lentiginous melanoma and melanoma of unknown primary site. The median survival after diagnosis of brain metastases was of 2.5 months. There was no significant difference with vemurafenib-treated patients in terms of incidence rate of brain metastasis, time of development and survival after diagnosis of cerebral metastases. This was the first study focused on the development of brain metastases under treatment with ipilimumab 3 mg/kg. Although ipilimumab is used for the treatment of brain metastases, it paradoxically did not seem to reduce the risk of developing brain metastases.